For more than 40 years, the NCI has supported a clinical trials infrastructure program to conduct early phase clinical trials across the US. As par of its efforts to enhance, facilitate, and expedite the process of early-phase drug development, the NCI created the NCI Experimental Therapeutics Program (NExT), which represents a joint early therapeutics development program between NCI intramural and extramural teams/institutions to prioritize a pipeline of NCI-driven targeted therapeutics. The NCI has now developed a comprehensive plan to transform the NCI-sponsored cooperative experimental therapeutics clinical trials program from a series of separate institutions conducting early-phase cancer treatment trials to a new consolidated, integrated Program, referred to as the NCI Experimental Therapeutics-Clinical Trials Network (ET-CTN). The University of Pittsburgh Cancer Institute (UPC) has been an NCI-designated comprehensive cancer center since 1990, and the UPCI has been involved in the NCI-U01 Phase I Early Drug Development Program since 1999. We now propose to be part of the new NCI ET-CTN as a Lead Academic Organization with the following specific aims: (1) to conduct early-phase experimental therapeutic clinical trials using single or combinations of novel agents from the NCI-CTP IND portfolio; (2) to participate on investigational agent-specific Project Teams to define the drug development plan; (3) to investigate the PK/PD aspects of the experimental agents and establish potential relationships between dose, schedule, exposure, and biological/antitumor effect; (4) to develop statistically appropriate clinical trial designs, including integral and integrated biomarker trials, accelerated titration, adaptive designs, and other design schemes; (5) to investigate special study populations with hepatic and/or renal dysfunction; (6) to evaluate data from related laboratory-based studies that assess drug-drug interactions; and (7) to evaluate translational endpoints in clinical trials of investigational agents. RELEVANCE: As a Lead Academic Organization of the NCI Experimental Therapeutics Clinical Trials Network, the UPCI plans to leverage its significant experience and leadership in early-phase clinical drug development and facilitate the early-phase clinical development of novel therapeutic agents and combinations that are of high priority to the NCI and the national interest. The long-term goal of this effort is to guide future disease specific clinical trials tha may have the potential to change the standard of cancer care in the US and worldwide